Silyl linker for solid phase organic synthesis of aryl-containing molecules

ABSTRACT

This invention relates to improved silyl linkers, methods for their preparation and their use in the solid phase synthesis of aromatic carbocycles, especially electron deficient aromatic carbocycles.

This application claims the benefit of U.S. Provisional Application No.60/017,955, filed May 20, 1996.

FIELD OF THE INVENTION

This invention relates to improved silyl linkers, methods for theirpreparation and their use in the solid phase synthesis of aromaticcarbocycles, especially electron deficient aromatic carbocycles.

BACKGROUND OF THE INVENTION

In the continuing search for new chemical moieties that can effectivelymodulate a variety of biological processes, the standard method forconducting a search is to screen a variety of pre-existing chemicalmoieties, for example, naturally occurring compounds or compounds whichexist in synthetic libraries or databanks. The biological activity ofthe pre-existing chemical moieties is determined by applying themoieties to an assay which has been designed to test a particularproperty of the chemical moiety being screened, for example, a receptorbinding assay which tests the ability of the moiety to bind to aparticular receptor site.

In an effort to reduce the time and expense involved in screening alarge number of randomly chosen compounds for biological activity,several developments have been made to provide libraries of compoundsfor the discovery of lead compounds. The chemical generation ofmolecular diversity has become a major tool in the search for novel leadstructures. Currently, the known methods for chemically generating largenumbers of molecularly diverse compounds generally involve the use ofsolid phase synthesis, in particular to synthesize and identify peptidesand peptide libraries. See, for example, Lebl et al., Int. J. Pept.Prot. Res., 41, p. 201 (1993) which discloses methodologies providingselectively cleavable linkers between peptide and resin such that acertain amount of peptide can be liberated from the resin and assayed insoluble form while some of the peptide still remains attached to theresin, where it can be sequenced; Lam et al., Nature, 354, p. 82 (1991)and (WO 92/00091) which disclose a method of synthesis of linearpeptides on a solid support such as polystyrene or polyacrylamide resin;Geysen et al., J. Immunol. Meth., 102, p. 259 (1987) which discloses thesynthesis of peptides on derivatized polystyrene pins which are arrangedon a block in such a way that they correspond to the arrangement ofwells in a 96-well microtiter plate; and Houghten et al., Nature, 354,p. 84 (1991) and WO 92/09300 which disclose an approach to de novodetermination of antibody or receptor binding sequences involvingsoluble peptide pools.

The major drawback, aside from technical considerations, with all ofthese methods for lead generation is the quality of the lead. Linearpeptides historically have represented relatively poor leads forpharmaceutical design. In particular, there is no rational strategy forconversion of a linear peptide into a non-peptide lead. As noted above,one must resort to screening large databanks of compounds, with eachcompound being tested individually, in order to determine non-peptideleads for peptide receptors.

In this respect, there has been increasing interest in the applicationof solid phase synthesis to the preparation of organic compounds,especially in the context of combinatorial chemistry and multiplesimultaneous synthesis. One of the limitations in the solid phaseapproach involves the linker by which the organic molecule is attachedto the solid support. Most linkers are based on protecting groupchemistry and require the presence of an appropriate functional group inthe target molecules being synthesized. Recently Plunkett and Ellman, J.Org. Chem. 1995, 60, 6006-6007 and Chenera et al., J. Amer. Chem. Soc.1995, in press (see also, WO 95/16712 published Jun. 22, 1995), havedescribed resin-bound aryl silane intermediates (1 and 2 shown below,wherein PS represents the polystyrene matrix and R represents the restof the organic molecule synthesized on the resin) in which the arylsilane bond is cleaved by strong acid or fluoride ion to release theunfunctionalized aryl moiety. ##STR1##

A modified version (see dotted box of resin-bound aryl silaneintermediate 3, above) of Chenera linker 2 was used in preparing anelection deficient aromatic carbocycle as shown in Scheme 1 (Compound4-Scheme 1). However, by using modified linker 3, an unexpectedalternate synthetic route was taken and the desired election deficientaromatic carbocycle 4-Scheme 1 was not recovered after neat TFA cleavagefrom the resin. Since the use of neat TFA for cleaving aromaticcarbocycles from a resin-bound aryl silane intermediate presents severalsynthetic advantages, the need for a silane linker useful in solid phasesynthesis for preparing election deficient aromatic carbocyles which canbe cleaved from a polymeric resin by neat TFA was demonstrated. As aresult, the improved aryl silane linker described herein was designed.

SUMMARY OF THE INVENTION

This invention relates to an improved novel silicon-based linker andpolymer resin and methods for preparing said linker and resin. Theimproved linker is particularly useful in the solid phase preparation ofaromatic carbocycles which contain election withdrawing substituents. Byutilizing the instant linker, solid phase synthesis of a single aromaticcarbocycle or a combinatorial library of derivatized aromaticcarbocycles, especially where the aromatic carbocycles are electrondeficient, is effectuated in that such carbocycles are easily cleavedfrom the resin-bound aryl silane intermediates so formed, by acidcatalyzed protodesilylation, e.g., with neat TFA.

One aspect of this invention relates to methods for preparing a compoundby resin-bound synthesis, wherein the compound is an aromatic carbocyclecomprising an aromatic carbon atom and at least one substituent X, A, Bor C that is not hydrogen or alkyl, said aromatic carbon atom having ahydrogen bound to it after cleavage from the resin. It will berecognized that the instant linker may be used in the solid phasesynthesis of a plurality of aromatic carbocycles using combinatorial ormultiple simultaneous synthesis methods known to the skilled artisan.

The aromatic carbocycles prepared using the improved silyl linker may beuseful as receptor ligands, particularly G-protein coupled receptorligands, enzyme inhibitors and channel blockers.

DETAILED DESCRIPTION OF THE INVENTION BRIEF DESCRIPTION OF FIGURES

FIG. 1: Shows the time course of vapor phase TFA cleavage of 2-Scheme 5.

FIG. 2: Shows yields from repeated vapor phase cleavage of an aliquot of2-Scheme 5.

The term "core structure(s)" is used herein at all occurrences to mean acore molecular structure(s) which is derived from compounds which havebeen shown to interact with a receptor, in particular, a G-proteincoupled receptor, and which is used as a template for designing thelibraries of compounds to be made. Core structures may be aromaticcarbocycles as defined below.

The term "library of compounds" is used herein at all occurrences tomean a series or plurality of compounds derivatized from their corestructure. Suitably, the core structure used for designing a library ofcompounds is an aromatic carbocycle. The libraries of compounds areuseful as screening tools for generating lead compounds which arepharmacophores that can be further modified pursuant to a drug discoveryeffort.

The term "combinatorial library" is used herein at all occurrences tomean a collection of compounds based upon a core structure, for example,an aromatic carbocycle structure, wherein the library contains adiscrete number of independently variable substituents, functionalgroups or structural elements, and further, wherein the library isdesigned so that, for the range of chemical moieties selected for eachof the independently variable substituents, compounds containing allpossible permutations of those substituents will be present in thelibrary. Thus, by way of illustration, if a core structure, labeled R,contains three independently variable substituents, labeled X, Y and Z,and if X is taken from m different chemical moieties, Y from n differentchemical moieties and Z from p different chemical moieties (wherein m, nand p are integers which define the size of the library, and which rangebetween 1 to 1000; preferably between 1 to 100; most preferably between1 to 20), then the library would contain m×n×p different chemicalcompounds and all possible combinations of X, Y and Z would be presenton the core structure R within that library. The methods for preparingcombinatorial libraries of compounds are such that the molecularlydiverse compound members of the libraries are synthesizedsimultaneously.

The term "aromatic carbocycle" is used herein at all occurrences to meana compound which comprises a single ring or a fused ring system,preferably 5-14 membered ring systems, and, for purposes herein,includes an optionally substituted biphenyl, composed of carbon atomshaving aromatic character, e.g., characterized by delocalized electronresonance and the ability to sustain a ring current and which ring orring systems may include one or more heteroatoms selected from oxygen,nitrogen or sulfur. The aromatic carbocycle may be optionallysubstituted by one or more substituents herein described as "substituentX", "substituent A", "substituent B" or "substituent C". When thearomatic carbocycle is a biphenyl, the substituents X, A, B or C may be,independently, on one or both rings. This is similarly so for otheraromatic carbocyclic rings or ring systems as defined above. It will berecognized by the skilled artisan that a large number of aromaticcarbocycles may be made using the silane linker of this invention,provided that the chemistry used to prepare the aromatic carbocycles iscompatible with the aryl silane bond, defined below. Suitable aromaticcarbocycles include, but are not limited to, optionally substitutedphenyl rings, optionally substituted naphthyl rings, optionallysubstituted tetrahydronaphthyl rings, optionally substituted anthracenylrings, optionally substituted 1-, 2- or 3- tetrahydrobenzazepines;optionally substituted 1,4-, 1,5-, or 2,4- tetrahydrobenzodiazepines;optionally substituted biphenyl tetrazoles; optionally substituted 1,3-or 1,4-diaminobenzene compounds; or optionally substituted 1,3- or1,4-aminocarboxyphenyl compounds. Suitably, the aromatic carbocyclesdescribed herein may serve as core structures, and therefore, astemplates for designing libraries of compounds to be screened aspharmaceutical agents. Suitably, the aromatic carbocycles are G-proteincoupled receptor ligands, channel blockers and/or enzyme inhibitors.

The terms "resin-bound synthesis" and "solid phase synthesis" are usedherein interchangeably to mean one or a series of chemical reactionsused to prepare either a single compound or a library of molecularlydiverse compounds, wherein the chemical reactions are performed on acompound, suitably, an aromatic carbocycle, which is bound to apolymeric resin support through an appropriate linkage, suitably, asilane linker.

The terms "resin," "inert resin," polymeric resin" or "polymeric resinsupport" are used herein at all occurrences to mean a bead or othersolid support such as beads, pellets, disks, capillaries, hollow fibers,needles, solid fibers, cellulose beads, pore-glass beads, silica gels,grafted co-poly beads, poly-acrylamide beads, latex beads,dimethylacrylamide beads optionally cross-linked with N,N'-bisacryloylethylene diamine, glass particles coated with a hydrophobic polymer,etc., i.e., a material having a rigid or semi-rigid surface. The solidsupport is suitably made of, for example, cross linked polystyreneresin, polyethylene glycol-polystyrene resin, and any other substancewhich may be used as such and which would be known or obvious to one ofordinary skill in the art. For purposes herein, it will be obvious tothe skilled artisan, that since the linker to the resin issilicon-based, the above terms mean any aliphatic or aromatic polymerwhich lacks functionality known to participate in the additionalsynthetic chemistry used for derivatizing the compound prepared by solidphase synthesis, and which is stable to conditions forprotodesilylation. Preferred polymer resins for use herein are theBenzhydrylamine resin (available commercially) and theAminomethylpolystyrene resin (available commercially). It should berecognized that the resin which is eventually coupled to the aryl silaneintermediate, defined infra, should comprise a pendant aminofunctionality.

The terms "silane linker" or "silane linker group" are used herein atall occurrences to mean the moiety which binds the aromatic carbocycleto the polymeric resin support, which linker comprises a silicon atombound to an alkyl chain comprising one or more methylene groups, saidalkyl chain having a terminal carbonyl moiety. A suitable silane linkerfor use in this invention comprises a moiety of the following formula--C(O)--(CH₂)_(n) -SiR^(a) R^(b),wherein R^(a) and R^(b) areindependently, C₁ to C₆ alkyl and n is an integer from 2 to 20.Preferably, R^(a) and R^(b) are independently, C₁ to C₄ alkyl, morepreferably, R^(a) and R^(b) are both methyl or ethyl, more preferablymethyl. Preferably n is 3.

The term "aryl silane compound" is used herein at all occurrences tomean an intermediate compound comprising an aromatic carbocycle havingan aromatic carbon and at least one substituent X, A, B or C that is nothydrogen or alkyl, wherein the aromatic carbon is bound to a silanelinker through an aryl silane bond.

The term "aryl silane bond" is used herein at all occurrences to meanthe bond between the aromatic carbon of an aromatic carbocycle and thesilicon atom of a silane linker. Suitably, after the resin-boundsynthesis is performed, this bond is cleaved by acid catalyzedprotodesilylation in order to decouple the aromatic carbocycle from theresin-bound aryl silane intermediate.

The term "resin-bound aryl silane intermediate" is used herein at alloccurrences to mean an intermediate wherein an aromatic carbocycle isdirectly bound to a silane linker, which linker is directly bound to apolymeric resin support. Therefore, it will be recognized that aresin-bound aryl silane intermediate is a moiety which couples anaromatic carbocycle to a polymeric resin support through a silanelinker. See, for example, Formula (I) infra.

The terms "substituent X," "substituent A," "substituent B," and"substituent C" are used herein at all occurrences to mean anon-nucleophilic substituent, including, but not limited to, hydrogen,halogen, alkyl, alkenyl, alkynyl, alkoxy, aryloxy, thioether (e.g.,-alkyl-S-alkyl-), alkylthio (e.g., alkyl-SH), C(O)R^(a), wherein R^(a)is hydrogen or alkyl, t-butoxyamino-carbonyl, cyano, nitro (--NO₂),aryl, heteroaryl, arylalkyl, alkyl disulfide (e.g., alkyl-S-S-), aryldisulfide (e.g., aryl-S-S-), acetal (alkyl(O-alkyl)₂), thioacetal(alkyl(S-alkyl)₂), fluorenylmethoxycarbonyl or orthoester (--C(OR)₃,wherein R is C₁ to C₄ alkyl). The substituents X, A, B and C are chosenindependently from one another. In addition, X, A, B and C can not allbe hydrogen and X, A, B and C can not all be alkyl. When the aromaticcarbocycle is a biphenyl, the substituents X, A, B or C may be,independently, on one or both rings. This is similarly so for otheraromatic carbocyclic rings or ring systems as defined above. As usedherein, modification of the substituents produces a derivatized aromaticcarbocycle. The nature of the substituents X, A, B and C, must becompatible with the reaction conditions used for modifying saidsubstituents without said conditions being capable of cleaving the arylsilane bond of the resin-bound aryl silane intermediate. Therefore, itwill be recognized that when modification of substituents X, A, B or Cby performing additional synthetic chemistry thereon utilizes reactionconditions such that the aryl silane bond is subject to cleavage, it isdesirable to choose a strong electron withdrawing group as thesubstituent(s). Additional synthetic chemistry can then be performed tomodify the substituent(s) without cleavage of the aryl silane bond.Subsequent to performing the additional synthetic chemistry to modifythe substituent(s), it is possible to cleave the aryl silane bond whichdecouples the aromatic carbocycle from the resin-bound aryl silaneintermediate. If desired, synthetic chemistry conventional in the artmay then be performed on the cleaved derivatized aromatic carbocycle toconvert the strong electron withdrawing group into a differentfunctionality, e.g., conversion of a nitro group into an amino groupusing known reaction conditions. Given this disclosure, the types ofsynthetic chemistry which are compatible with the goal of derivatizingthe resin-bound aromatic carbocycle, without also cleaving the arylsilane bond of the resin-bound aryl silane intermediate, will be obviousto one of ordinary skill in the art.

The term "additional synthetic chemistry" is used herein at alloccurrences to mean one or a series of chemical reactions which areperformed on the resin-bound aryl silane intermediate, in particular tomodify or derivatize substituents X, A, B and C, prior to cleavage ofthe aromatic carbocycle from the resin-bound aryl silane intermediate,wherein said chemical reactions are compatible with and non-reactivewith the aryl silane bond, especially silicon in the presence of anamide, and may be used to prepare derivatives of the aromaticcarbocycle. It will be recognized by the skilled artisan that theadditional synthetic chemistry performed on the resin-bound aryl silaneintermediate is done so prior to cleavage of the aryl silane bond.Chemical reactions which are compatible with the resin-bound aryl silaneintermediate, are reactions which effectuate the swelling of thepolymeric resin thereby allowing penetration of the reagents to reactwith the aromatic carbocycle. Chemical reactions which are reactive withthe aryl silane bond, i.e., they cause cleavage of the aryl silane bond,and therefore are not among the additional synthetic chemistry that maybe used in the methods of this invention, are for example, chemicalreactions which use strongly acidic conditions or strong electrophilicoxidizing agents (e.g., benzoyl peroxide under acidic conditions).

The term "G-protein coupled receptor(s)" is used herein at alloccurrences to mean a 7-transmembrane receptor using G-proteins as partof their signaling mechanism, including, but not limited to muscarinicacetylcholine receptors, adenosine receptors, adrenergic receptors,IL-8R receptors, dopamine receptors, endothelin receptors, histaminereceptors, calcitonin receptors, angiotensin receptors and the like.

The term "assay" is used herein at all occurrences to mean a bindingassay or a functional assay known or obvious to one of ordinary skill inthe art, including, but not limited to, the assays disclosed herein

The term "alkyl" is used herein at all occurrences to mean a straight orbranched chain radical of 1 to 20 carbon atoms, unless the chain lengthis limited thereto, including, but not limited to methyl, ethyl,n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and thelike. Preferably the alkyl chain is 1 to 10 carbon atoms in length, morepreferably 1 to 8 carbon atoms in length.

The term "alkenyl" is used herein at all occurrences to mean a straightor branched chain radical of 2-20 carbon atoms, unless the chain lengthis limited thereto, including, but not limited to, ethenyl, 1-propenyl,2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like.Preferably, the alkenyl chain is 2 to 10 carbon atoms in length, morepreferably, 2 to 8 carbon atoms in length.

The term "alkynyl" is used herein at all occurrences to mean a straightor branched chain radical of 2-20 carbon atoms, unless the chain lengthis limited thereto, wherein there is at least one triple bond betweentwo of the carbon atoms in the chain, including, but not limited to,acetylene, 1- propylene, 2-propylene, and the like. Preferably, thealkynyl chain is 2 to 10 carbon atoms in length, more preferably, 2 to 8carbon atoms in length.

In all instances herein where there is an alkenyl or alkynyl moiety as asubstituent group, the unsaturated linkage, i.e., the vinylene oracetylene linkage is preferably not directly attached to a nitrogen,oxygen or sulfur moiety.

The term "alkoxy" is used herein at all occurrences to mean a straightor branched chain radical of 1 to 20 carbon atoms, unless the chainlength is limited thereto, bonded to an oxygen atom, including, but notlimited to, methoxy, ethoxy, n- propoxy, isopropoxy, and the like.Preferably the alkoxy chain is 1 to 10 carbon atoms in length, morepreferably 1 to 8 carbon atoms in length.

The terms "cycloalkyl" and "cyclic alkyl" are used herein at alloccurrences to mean cyclic radicals, preferably comprising 3 to 10carbon atoms which may be mono- or bicyclo- fused ring systems which mayadditionally include unsaturation, including, but not limited to,cyclopropyl, cyclopentyl, cyclohexyl, 1,2,3,4-tetrahydronaphthyl, andthe like.

The terms "aryl" or "heteroaryl" are used herein at all occurrences tomean 5-14 membered optionally substituted aromatic ring(s) or ringsystems which may include bi- or tri-cyclic systems and one or moreheteroatoms, wherein the heteroatoms are selected from oxygen, nitrogenor sulfur. Representative examples include, but are not limited to,phenyl, naphthyl, pyridyl, quinolinyl, thiazinyl, isoquinoline,imidazole, 3,4-dimethoxyphenyl, 3,4-methylenedioxyphenyl,3,4-dimethoxybenzyl, 3,4-methylenedioxy-benzyl, benzhydryl,1-naphthylmethyl, 2-naphthylmethyl, fluorenyl, biphenyl-4-methyl,furanyl, and the like.

The term "heteroatom" is used herein at all occurrences to mean anoxygen atom ("O"), a sulfur atom ("S") or a nitrogen atom ("N"). It willbe recognized that when the heteroatom is nitrogen, it may form an NR¹R² moiety, wherein R¹ and R² are, independently from one another,hydrogen or C₁ to C₈ alkyl, or together with the nitrogen to which theyare bound, form a saturated or unsaturated 5-, 6-, or 7-membered ring.

The terms "arylalkyl" and "heteroarylalkyl" are used herein at alloccurrences to mean an aryl or heteroaryl moiety, respectively, that isconnected to a C₁₋₈ alkyl moiety as defined above, such as, but notlimited to, benzyl.

The term "5- 6-, or 7-membered ring" is used herein at all occurrencesto mean that substituents R¹ and R², together with the nitrogen to whichthey are bound, form a saturated or unsaturated ring structurecontaining at least one additional heteroatom selected from oxygen,nitrogen or sulfur, including, but not limited to morpholine,piperazine, piperidine, pyrolidine, pyridine, and the like.

The term "heterocyclic" is used herein at all occurrences to mean asaturated or wholly or partially unsaturated 4-10 membered ring systemin which one or more rings contain one or more heteroatoms selected fromthe group consisting of O, N, or S; including, but not limited to,pyrrolidine, piperidine, piperazine, morpholine, imidazolidine,pyrazolidine, benzodiazepines, and the like.

The term "halogen" is used herein at all occurrences to mean chloro,fluoro, iodo and bromo.

The term "Ph" is used herein at all occurrences to mean phenyl.

The term "optionally substituted" is used herein at all occurrences tomean that the optionally substituted moieties may or may not besubstituted with one to three various functional groups including,alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclogroups arylalkyl, heteroarylalkyl, halogen, cyano, --(CR¹¹ R¹²)_(n)-C(O)R'"; --(CR¹¹ R¹²)_(n) -NO₂ ; --(CR¹¹ R¹²)_(n) -OR'; (CR¹¹ R¹²)_(n)-SR'"; --(CR¹¹ R¹²)_(n) -N(R')₂ ; --(CR¹¹ R¹²)_(n) -NHC(O)R'"; --(CR¹¹R¹²)_(n) -CO₂ R'"; --(CR¹¹ R¹²)_(n) -CON(R'")₂ ; --(CR¹¹ R¹²)_(a)(C═C)_(b) (CR¹¹ R¹²)_(c) Z, or (CR¹¹ R¹²)_(a) (C═C)_(b) W'(CR¹¹ R¹²)_(c)Z'; wherein Z' is C(O)R', CO₂ R'", NO₂ ; OR'"; S R'"; N(R'")₂,NHC(O)R'"; or CON(R'")₂ ; a is 0 or 1, b is 0 to 10 and c is 0 to 10,preferably a=b=c is less than 10; W' is N or S; R'" is hydrogen, (C₁-C₄) alkyl, aryl, arylalkyl, or heteroaryl; and R¹ and R¹² areindependently hydrogen or a branched or straight chain C₁ to C₆ alkyl,alkenyl or alkynyl; and, for purposes herein, n is 0 or is an integerfrom 1 to 10. It is recognized that these substituents may be furthersubstituted by groups similar to those indicated above herein to givesubstituents such as halo-substituted alkyl (e.g., --CF₃),aryl-substituted alkyl, alkoxy-substituted alkyl and the like. Forexample, in the term (CR¹¹ R¹²)_(n) -N(R'")₂, n is 1, R¹¹ is --CH₂CH═CH₂, R¹² is hydrogen, one of R'" is hydrogen and one of R'" isbenzyl; in the term --(CR¹¹ R¹²)_(n) SR'", n is 1, R'" is phenyl, R¹² ishydrogen, R¹¹ is a substituted alkyl, specifically a methyl substitutedby --COOR'" and R'" is hydrogen, methyl or ethyl; in the term alkenyl,the alkenyl moiety may be substituted by --(CR¹¹ R¹²)_(n) -C(O)R'" or--(CR¹¹ R¹²)_(n) -CO₂ R'", wherein R'" is hydrogen, methyl or ethyl; inthe term (CR¹¹ R¹²)_(a) (C═C)_(b) (CR¹¹ R¹²)_(c) Z', a is 1, b is 1, cis 0, Z' is NR'", R¹¹ and R¹² are H and R'" is benzyl; in the term (CR¹¹R¹²)_(a) (C═C)_(b) W'(CR¹¹ R¹²)_(c) Z', W' is N and a is 1, b is 1, c is0, Z' is NR'", R¹¹ and R¹² are H and R'" is benzyl.

Preferred optional substituents for use herein include alkyl, alkenyl,alkoxy, cyano, NO₂, halogen, preferably bromine, --(CR¹¹ R¹²)_(n)C(O)R'", --(CR¹¹ R¹²)_(n) -SR'", --(CR¹¹ R¹²)_(n) -N(R'")₂ and aryl,preferably phenyl. More preferably, the optional substituents are C₁ toC₁₀ alkyl, C₁ to C₁₀ alkoxy, cyano, C(O)R'", NO₂, halogen, and aryl.

In contrast to the resins and linkers known in the art, the instantpolymeric resins and silane linkers are particularly useful ineffectuating the cleavage of an aromatic carbocycle from a polymericresin support while leaving a hydrogen at the cleavage position.

In one aspect, the invention is in a method for preparing a compound byresin-bound synthesis, wherein said compound is an aromatic carbocyclecomprising an aromatic carbon atom and at least one substituent that isnot hydrogen or alkyl, said method comprising the steps of: (i)attaching the aromatic carbon to a polymeric resin support through asilane linker to give a resin-bound aryl silane intermediate; and (ii)performing additional synthetic chemistry on the substituent so that thearomatic carbocycle is derivatized. The derivatized resin-bound arylsilane intermediate may be stored for further derivatization of thesubstituents. Suitably, the aromatic carbocycle is biphenyl, phenyl,naphthyl or anthracenyl. Suitably, the aromatic carbocycle has at leastone substituent that is X, A, B or C, as defined above, to bederivatized by additional synthetic chemistry. A compound prepared bythis method remains as a resin-bound aryl silane intermediate, whichresin-bound intermediate may be screened in a suitable assay developedfor determining pharmaceutical activity.

Alternatively, the derivatized aromatic carbocycle may be decoupled fromthe resin-bound aryl silane intermediate by a further step comprisingcleaving the resin-bound aryl silane intermediate at the aryl silanebond so that the decoupled aromatic carbocycle resulting from thecleavage has a hydrogen on the aromatic carbon where it was boundthrough the silane linker. After this step, the decoupled aromaticcarbocycle may be screened in a suitable assay developed for determiningpharmaceutical activity.

As described above, the additional synthetic chemistry performed inorder to modify the substituents X, A, B or C must be such that thearomatic carbocycle is derivatized without cleaving the aryl silane bondof the resin-bound aryl silane intermediate.

According to this invention, the aromatic carbocycle is bound to apolymeric resin support through the improved silyl linker to give aresin-bound aryl silane intermediate. In particular, the aromaticcarbocycle is bound to the resin through a silane linker groupcomprising the following moiety: C(O)--(CH₂)_(n) -Si-R^(a) R^(b),wherein R^(a) and R^(b) are independently, C₁ to C₆ alkyl and n is aninteger from 2 to 20. For purposes herein, the aromatic carbon atom ofthe aromatic carbocycle is bound directly to a silicon atom of thesilane linker. Preferably, R^(a) and R^(b) are independently, C₁ to C₄alkyl, more preferably, R^(a) and R^(b) are both methyl or ethyl, morepreferably R^(a) and R^(b) are both methyl. Preferably n is the integer3.

Useful intermediates of the invention are the resin-bound aryl silaneintermediates of Formula (I). The compounds of Formula (I) are furthermodified by performing additional synthetic chemistry thereon.Preferably, an aryl silane compound is formed as a first intermediate,which intermediate is then coupled (using conventional techniques) to apolymeric resin support such as benzhydrylamine resin, to give acompound of Formula (I): ##STR2## wherein R^(a) and R^(b), independentlyfrom one another, are C₁ to C₆ alkyl; X, A, B and C are, independentlyfrom one another, hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy,alkylthio, C(O)R^(d), wherein R^(d) is hydrogen or alkyl,t-butoxyaminocarbonyl, cyano, nitro, aryl, heteroaryl, arylalkyl, alkyldisulfide, aryl disulfide, acetal, fluorenylmethoxycarbonyl ororthoester group, provided that X, A, B and C can not all be hydrogenand X, A, B and C can not all be alkyl; and n is an integer from 2 to20.

In all cases, after the aromatic carbocycle portion of the resin-boundaryl silane intermediate is modified by the additional syntheticchemistry, the derivatized aromatic carbocycle may be cleaved from theresin-bound aryl silane intermediate at the aryl silane bond or it mayremain as a resin-bound aryl silane intermediate. Neat TFA or TFA vaporare the most preferred reagents to effectuate cleavage of the arylsilane bond.

In yet another aspect, this invention is in a method for preparing alibrary of diverse resin-bound aromatic carbocycles each comprising anaromatic carbon atom and at least one substituent that is not hydrogenor alkyl, said method comprising the steps of: (i) attaching thearomatic carbon atom of each of a plurality of aromatic carbocycles toan individual polymeric resin support through a silane linker to give aplurality of resin-bound aryl silane intermediates; (ii) optionallydividing said resin-bound aryl silane intermediates into a plurality ofportions; (iii) performing additional synthetic chemistry on thesubstituents so that the aromatic carbocycle is derivatized; and (iv)optionally recombining the portions. Suitably, the substituents on thearomatic carbocycle which are to be derivatized are X, A, B or C asdefined above.

For example, a plurality of aromatic carbocycles each comprising anaromatic carbon atom and having at least one substituent X, A, B or Cthat is not hydrogen or alkyl, are each attached to an individualpolymer resin support through a silane linker to give a plurality ofresin-bound aryl silane intermediates. In a first step modification tothe substituent(s) on the aromatic carbocycle, the plurality ofresin-bound aryl silane intermediates may be reacted with one or morereagents in one reaction vessel. Alternatively in a first stepmodification, aliquots of the resin-bound aryl silane intermediates maybe reacted with one or more reagents and then the resultant products aremixed together to form a library of derivatized aromatic carbocycles.Preferably, the reagent(s) used in this first step modification willmodify only a single substituent X, A, B or C.

This first modified/derivatized library may then be further derivatizedby repeating the process of dividing and recombining the derivatizedresin-bound aryl silane intermediates formed by the additional syntheticchemistry. It will be obvious to the skilled artisan that theresin-bound aryl silane intermediates may be divided into portions atany point during the synthetic scheme. The portions may be recombined atany point during the scheme or, further iterations may be applied ifmore derivatization is required. For example, after a first stepmodification where the aliquots were divided and reacted with one ormore appropriate reagents, the derivatized aliquots may be recombinedand reacted with one or more additional reagents in one reaction vessel.Alternatively, each aliquot may be subdivided into further aliquots andreacted as described herein.

Therefore, it will be obvious to the skilled artisan that the steps ofdividing the portions, performing additional synthetic chemistry andrecombining the portions, may each be carried out more than once. Thesteps of optionally dividing and recombining the resin-bound aryl silaneintermediates into portions are for purposes of varying thederivatization, depending upon the type of diversity required for thelibrary of end-product aromatic carbocycles being prepared by thecombinatorial synthesis. Suitably, when the libraries of the inventionare prepared according to the instant disclosure, each polymeric resinsupport bears a single (derivatized) aromatic carbocycle species createdby the additional synthetic chemistry performed on the resin-bound arylsilane intermediate.

The instant silyl linker was developed as an improvement over knownsilyl linkers for use in solid phase combinatorial or multiplesimultaneous synthesis. As described above, the inventors wereinterested in the solid phase synthesis of molecules of the generalstructure represented by 4-Scheme 1, and the use of an aryl silanelinker as disclosed in WO 95/16712 (see dotted box in structure 2 aboveat page 2) provided an attractive synthetic route as shown in Scheme 1.The design of resin-bound aryl silane intermediate 2, shown above atpage 2, which is attached to Merrifield resin via an ether linkage, wasmodified in order to introduce a carboxylic acid functionality whichcould be coupled to benzhydrylamine (BHA) resin to give resin-bound arylsilane intermediate 3, shown above at page 2. Modifying the linkerportion of 2 was thought to afford several advantages. First,intermediate carboxylic acid 1-Scheme 1, could be prepared in solutionand rigorously purified and characterized before attachment to the resinto form the resin-bound aryl silane intermediate. Attachment to the BHAresin would be via an amide bond formation reaction, a highly optimizedsolid phase reaction which allows for monitoring the extent ofattachment of material to resin by the ninhydrin test (Kaiser, et al.,Anal. Biochem. 1970, 34, 594-598) and then driven to completion. Theresulting resin construct was expected to be both homogeneous and ofknown loading, both of which facilitate analysis of the subsequentsynthetic reactions performed. ##STR3##

However, during initial synthetic experiments, unexpected difficultieswere encountered in isolating the expected intermediates after neat TFAcleavage from the resin. In fact, neither benzyl alcohol from cleavageof 2a-Scheme 1 nor benzaldehyde from cleavage of 2b-Scheme 1 were ableto be isolated. An investigation of the cleavage chemistry indicatedthat an unexpected alternative cleavage pathway was occurring whenresin-bound aryl silane intermediate 3 (see structure on page 2) wasused as in Scheme 1. Because of this unexpected result, the linkerportion of intermediate 3 (see dotted box on intermediate at page 2supra) was modified to give a novel linker as depicted in the dotted boxarea of resin-bound aryl silane intermediate 4 (page 2 supra). Usingthis novel linker, all the requisite chemistry shown in Scheme I wassuccessfully demonstrated.

Before developing the improved silyl-linker of this invention, a linkermodeled after the silyl linkers disclosed in WO 95/16712 (structure 3,supra) was proposed for synthesizing compound 8-Scheme 2. 4-Bromobenzylalcohol was protected as the triisopropylsilyl ether 2-Scheme 2, whichwas then converted to the Grignard reagent and reacted with(bromomethyl)-chlorodimethylsilane to give the bromomethylsilane3-Scheme 2. Treatment of 3-Scheme 2 with methyl3-(4-hydroxyphenyl)propionate and potassium carbonate in refluxing2-butanone gave the silylmethyl phenyl ether 4-Scheme 2, which wasdeprotected to give the benzyl alcohol 5-Scheme 2. Oxidation of 5-Scheme2 with manganese dioxide to the aldehyde 6-Scheme 2 followed byreductive amination with tyramine and acetylation with acetic anhydridegave the desired model compound 8-Scheme 2. ##STR4##

Compound 8-Scheme 2 was then subjected to several different cleavagereactions. The results are summarized in Scheme 3. Treatment of 8-Scheme2 with neat TFA at room temperature did not give the desired compound3-Scheme 3. The phenol 1-Scheme 3, which arises from an alternativecleavage of the carbon-oxygen bond in the linker, was instead isolatedin quantitative yield along with a second product which has beententatively assigned to the structure 2-Scheme 3 based on ¹ H NMR andmass spectral data. This cleavage pattern and distribution of productshas been observed previously in the cleavage of silylmethyl methylethers with trimethylsilyl iodide (Cunico, R. F.; Gill, H. S.Organometallics 1982, l, 1-3). ##STR5##

Interestingly, the desired product 3-Scheme 3 was obtained followingtreatment of 8-Scheme 2 with HF or CsF, although small amounts of1-Scheme 3 and 2-Scheme 3 were also detected by HPLC analysis of thecrude cleavage reaction mixture. These conditions, however, are lessattractive from the point of view of combinatorial or simultaneousmultiple synthesis. HF can be difficult to handle and requires arelatively complex apparatus. After CsF cleavage, the compound isobtained as a mixture containing any excess CsF along with other cesiumsalts in a relatively non-volatile solvent. The effective use ofcombinatorial or multiple simultaneous synthesis requires that thecleavage chemistry leave the minimum amount of extraneous residue behindand that the workup be minimal, preferably just evaporation of avolatile cleavage reagent. The instant silyl linker solves suchsynthetic problems and allows for cleavage of the resin-bound arylsilane intermediate with neat TFA.

In solution, compound intermediate 5-Scheme 4 was readily preparedaccording to Scheme 4. The benzyl alcohol silyl propionate 2-Scheme 4was prepared from the corresponding 4-bromobenzyl alcohol in six steps.Treatment of 3-Scheme 2 with the sodium salt of dimethyl malonate gave1-Scheme 4, which was deprotected to the benzyl alcohol and thendemethoxycarbonylated with lithium chloride in DMSO and water to give2-Scheme 4. Oxidation to the benzaldehyde 3-Scheme 4 with MnO₂,reductive amination with tyramine and acetylation of the secondary aminewith acetic anhydride gave the silyl linked compound 5-Scheme 4.Treatment of 5-Scheme 4 with neat TFA produced the desired productcompound 3-Scheme 3 with no evidences of any side reactions. ##STR6##

Application of the improved silyl linker to solid phase chemistry wasshown to be effective by preparing 3-Scheme 3 as shown in Scheme 5.5-Scheme 4 was saponified and the resulting free acid 1-Scheme 5 wascoupled to BHA resin to give 2-Scheme 5. Treatment of 2-Scheme 5 withneat TFA for 40 h at room temperature gave a quantitative yield of3-Scheme 3. As is often the case with solid phase cleavage reactions,the crude product was quite clean, with no detectable impurities orcontamination by starting material. ##STR7##

In addition to neat TFA, TFA vapor has also been used to cleavecompounds from acid-labile resins (Jayawickreme et al., Proc. Natl.Acad. Sci. USA 1994, 91, 1614-1618). The use of TFA vapor affords someadvantages in combinatorial or multiple synthetic strategies. Withliquid TFA (either neat or containing scavengers), the compound iscleaved off the resin and extracted into the TFA solution. Thisnecessitates the filtering and handling of a hazardous, corrosive andvolatile material. After cleavage with TFA vapor, however, the compoundsremain adsorbed to the resin and are eluted with a solvent which is bothless dangerous to handle and more suitable for biological screening. Theapparatus required is quite simple. Beads are distributed into smallsintered glass funnels or 96-well filter plates, which are suspended ina TLC chamber or desiccator containing a small volume of TFA at thebottom. After the desired reaction time, the funnels or plates aresimply removed and placed in a vacuum desiccator to remove residual TFA.The beads can then be extracted and eluted with a solvent such asmethanol, acetic acid, or dimethylformamide.

An experiment supporting the kinetics of cleavage of the compound offthe resin was conducted by exposure of the resin-bound aryl silaneintermediate 2-Scheme 5 to a single exposure to TFA. The time course ofvapor phase TFA cleavage of 2-Scheme 5 is shown in FIG. 1. Weighedaliquots of 2-Scheme 5 were cleaved for various times, extracted with 2%MeOH in CHCl₃ and the amount of 3-Scheme 3 obtained was quantitated byHPLC. The time course for vapor phase cleavage is quite similar to thesolution cleavage results, with a t_(1/2) of about 13 h and nearlyquantitative cleavage occurring by 40 h at room temperature.

The time course of cleavage and the relatively substantial amount ofcleavage, approximately 30%, which had occurred in the first six hoursof reaction suggested that this resin might be useful for controlledpartial release of compound from the resin. Partial release is useful insingle bead-associated combinatorial screening. See, Jayawickreme etal., Proc. Natl. Acad. Sci. USA 1994, 91, 1614-1618 and Salmon et al.,Proc. Natl. Acad. Sci. USA 1993, 90, 11708-11712. A portion of thecompound can be released from a single bead, eluted and assayed assoluble material. Sufficient compound remains on the bead for subsequentidentification. (See, Zambias et al., Tet. Lett. 1994, 35, 4283-4286 andKrebs et al., Biochem. 1995, 34, 720-723). Partial cleavage has beenachieved in a rigorous fashion by the simultaneous use of orthogonallycleavable linkers, but it has also been effected by limited exposure ofacid-labile linkers to TFA vapor.

It will be recognized that when the instant silyl linker is used insolid phase synthesis, partial cleavage may be achieved. For example, analiquot of 2-Scheme 5 was subjected to several rounds of treatment withTFA vapor. After each partial cleavage, the released aromatic carbocycle3-Scheme 3 was eluted from the resin and quantified by HPLC. The resultsare shown in FIG. 2. Approximately 25% of the available 3-Scheme 3 wasreleased from the resin in each of the first two 6-hour exposures to TFAvapor and an additional 10% was released in the third partial cleavage.These numbers are in good agreement with the time course of cleavage inFIG. 1 and indicate that this linker would perform suitably in a partialrelease strategy.

Scheme 6 incorporates all the chemistry envisioned in Scheme 1 using theimproved silyl linker described herein. Scheme 6 also demonstrates someadditional synthetic chemistry within the scope of this invention. Thechemistry was monitored by elemental analysis and magic angle spinningproton NMR. The benzyl alcohol aryl silane compound 2-Scheme 4 wassaponified, coupled to BHA resin and smoothly converted to the benzylbromide 3-Scheme 6 with CBr₄ and triphenylphosphine. This resin-boundbenzyl bromide aryl silane intermediate was then used to alkylatetyramine to produce the secondary amine 4-Scheme 6. This reactiondemonstrates the power of solid phase synthesis. In a solution reaction,one would expect to obtain a mixture of mono- and di-alkylatedtyramines. Using an excess of tyramine and a resin-bound alkylatingagent, dialkylation is effectively suppressed and the desired product isobtained cleanly. Acetylation with acetic anhydride to give 5-Scheme 6followed by Mistunobu reaction with dimethylaminoethanol using DIADinstead of DEAD to avoid formation of any ethyl ether (Krchnak et al.,M. Tet. Lett. 1995, 36, 6193-6196) gave the resin-bound aryl silaneintermediate 6-Scheme 6. The final product 7-Scheme 6 was obtained inquantitative yield based on starting resin-bound aryl silaneintermediate 2-Scheme 6 after cleavage with TFA vapor. ##STR8##

Experimental Section

Abbreviations used herein have the following meanings, unless otherwisestated. Benzhydrylamine resin ("BHA"); Dicyclohexylcarbodiimide ("DCC");1-hydroxybenzotriazole hydrate ("HOBt"); Triphenylphosphine ("Ph₃ P");diethyl azodicarboxylate ("DEAD"); Diisopropyl azodicarboxylate("DIAD"); triisopropylsilyl chloride ("TIPS-Cl"); Magic angle spinning("MAS"); Trifluoroacetic acid ("TFA"); Tetrahydrofuran ("THF");Triethylamine ("Et₃ N"); Acetic acid ("AcOH"); Methanol ("MeOH"); andDimethylsulfoxide ("DMSO"). Reagent grade solvents and commercialreagents were used without additional purification. THF was distilledfrom sodium ketyl. Proton NMR spectra were obtained at 250 MHz on aBrucker AM 250 spectrometer and at 400 MHz on a Brucker AMX 400spectrometer. Magic angle spinning proton NMR was obtained on a Varian500 MHz spectrometer equipped with a magic angle spinning nanoprobe.Chemical shifts are reported relative to tetramethylsilane. Electrospraymass spectra were obtained on a Fisons Instruments VG Biotechspectrometer. Infrared spectra were obtained on a Nicolet Impact 400DFourier transform infrared spectrophotometer. HPLC was performed on aBeckman System Gold chromatograph.

O-Triisopropylsilyl-4-bromobenzyl alcohol (2-Scheme 2)

To a solution of 4-bromobenzyl alcohol (50.07 g, 268 mmol) in DMF (500mL) was added with stirring, under Ar, imidazole (40 g, 588 mMol)followed by triisopropylsilylchloride (57.3 mL, 268 mMol). Afterstirring for 24 h at room temperature the reaction was evaporated todryness, taken up in hexane (500 mL), washed with aq. 1N hydrochloricacid (500 mL), brine (500 mL), dried (MgSO₄), and evaporated to give2-Scheme 2 as a clear oil. (91.72 g, 99%): TLC r_(f) 0.71 (silica, 50:1hexane:ethyl acetate); GC rt 2.98 (HP 530μ×20 m methylsilicone column,He carrier flow 20 mL/min., 150° C. init. temp., 10° C./min. rate, 250°C. final temp., 2 min. final time); ¹ H NMR (400 MHz, CDCl₃) δ 1.08(18H, d, J=6.4 Hz), 1.14 (3H, m), 4.78 (2H, s), 7.22 (2H, d, J=8.4 Hz),7.45 (2H, d, J=8.4 Hz).

[Dimethyl-4-(triisopropylsilyloxymethyl)phenylsilyl]methylbromide(3-Scheme 2)

To a stirred mixture of Mg turnings (2.22 g, 91 mmol) in THF (100 mL)was added 1,2-dibromoethane (300 μL, 3.5 mmol). The mixture was stirredunder Ar and heated to 70° C. (reflux). After 5 min. the reaction wascooled to room temperature and a solution of 2-Scheme 2 (30 g, 87.4mMol) in THF (100 mL) was added in one portion. The reaction was thenslowly heated to reflux (slightly exothermic) and allowed to stir foranother 5 h until all the Mg was consumed. The resultant pale brownsolution was then cooled to -78° C. and a solution of(bromomethyl)chlorodimethylsilane (15 mL, 110 mL) in THF (50 mL) wasadded slowly over 5 minutes. After stirring for 1 h the reaction wasallowed to warm to room temperature and stirred for an additional 16 h.The reaction was evaporated to dryness, taken up in hexane (500 mL),washed with cold aq. 1N hydrochloric acid (500 mL), brine (500 mL),dried (MgSO₄) and evaporated. Purification by Kugelrohr distillation(140-150° C.) gave 3-Scheme 2 as a clear oil. (23.54 g, 65%): TLC r_(f)0.53 (silica, 50:1 hexane:ethyl acetate); GC rt 8.27 (HP 530-20 mmethylsilicone column, He carrier flow 20 mL/min., 150° C. init. temp.,10° C./min. rate, 250° C. final temp., 2 min. final time); ¹ H NMR (400MHz, CDCl₃) δ 0.43 (6H, s), 1.12 (18H, d, J=6.6 Hz), 1.18 (3H, m), 2.63(2H, s), 7.38 (2H, d, J=8.0 Hz), 7.51 (2H, d, J=8.0 Hz).

Methyl3-[[dimethyl-4-(triisopropylsilyloxymethyl)phenylsilyl]methyloxy-phenyl]propionate(4-Scheme 2)

To a stirred solution of 3-Scheme 2 (29.57 g, 71 mmol) and methyl3-(4-hydroxyphenyl)-propionate (12.80 g, 71 mMol) in 2-butanone (200 mL)was added K₂ CO₃ (9.8 g, 71 mMol). The suspension was stirred under Arat reflux (80° C.) for 72 h, cooled to room temperature and evaporatedto dryness. The residue was taken up in ethyl acetate (500 mL) andwashed with aq. 1N HCl (500 mL), brine (500 mL), dried (MgSO₄) andevaporated to dryness. Purification by flash chromatography (silica. 5%ethyl acetate/hexane) gave 4-Scheme 2 (22.06 g, 60%) as a clear oilalong with recovered starting material. (10.43 g, 35%): TLC r_(f) 0.49(silica 10% ethyl acetate/hexane); ¹ H NMR (400 MHz, CDCl₃) δ 0.41(6H,s), 1.09 (18H, d, J=6.5 Hz), 1.17 (3H, m), 2.58 (2H, t), 2.88 (2H,t), 3.66 (3H, s), 3.73 (2H, s), 4.84 (2H, s), 6.88 (2H, d, J=8.7 Hz),7.09 (2H, d, J=8.7 Hz), 7.37 (2H, d, J=8.0 Hz), 7.56 (2H, d, J=8.0 Hz).

Methyl3-[[dimethyl-4-(hydroxymethyl)phenylsilyl]methyloxyphenyl]-propionate(5-Scheme 2)

To compound 4-Scheme 2 (29.76 g, 57.8 mmol) was added a solution ofacetic acid, THF, water (3:1:1) (500 mL). The resulting mixture wasstirred at 45° C. for 24 h under an Ar atmosphere, cooled to roomtemperature and evaporated to dryness. Purification by flashchromatography (silica, 30% ethyl acetate/hexane) gave 5-Scheme 2 as awhite crystaline solid. (16.47 g, 79%): TLC r_(f) 0.29 (silica 30% ethylacetate/hexane); ¹ H NMR (400 MHz, CDCl₃) δ 0.41 (6H, s), 1.78 (1H, brs), 2.58 (2H, t), 2.88 (2H, t), 3.65 (3H, s), 3.74 (2H, s), 4.69 (2H,s), 6.88 (2H, d, J=8.6 Hz), 7.08 (2H, d, J=8.6 Hz), 7.38 (2H, d, J=7.8Hz), 7.60 (2H, d, J=7.8 Hz).

Methyl 3-[(dimethyl-4-formylphenylsilyl)methyloxyphenyl]propionate(6-Scheme 2)

To a stirred solution of 5-Scheme 2 (4.0 g, 11.2 mmol) in CH₂ Cl₂ (150mL) was added MnO₂ (5.0 g, 57.5 mMol). The suspension was heated toreflux under Ar and stirred for 16 h. After cooling to room temperaturethe reaction mixture was filtered through a pad of celite and rinsedwith CH₂ Cl₂ (50 mL). The filtrate was evaporated to give 6-Scheme 2 asa white crystalline solid. (3.74 g, 94%); TLC r_(f) 0.47 (silica, 30%ethyl acetate/hexane); ¹ H NMR (400 MHz, CDCl₃) δ 0.46 (6H, s), 2.59(2H, t), 2.89 (2H, t), 3.66 (3H, s), 3.77 (2H, s), 6.88 (2H, d, J=8.5Hz), 7.09 (2H, d, J=8.5 Hz), 7.78 (2H, d, J=7.9 Hz), 7.86 (2H, d, J=7.9Hz), 10.03 (1H, s).

Methyl3-[dimethyl-4-[N-[2-(4-hydroxyphenyl)ethyl]aminomethyl]phenylsilyl]methyloxyphenyl]propionate(7-Scheme 2)

To a stirred solution of methyl 6-Scheme 2 (1.03 g, 2.9 mmol) in drymethanol (30 mL) were added tyramine (0.5 g, 3.6 mMol) and acetic acid(0.22 mL, 3.6 mMol). The reaction was stirred for 2 h, then NABH₃ CN(0.23 g, 3.6 mMol) was added portionwise over 15 min. (foaming). Afterstirring for 16 h the reaction was evaporated to dryness, taken up inCHCl₃ (100 mL), washed with brine (100 mL), dried (Na₂ SO₄) andevaporated. Purification by flash chromatography (silica, 3-5%methanol/CHCl₃) gave 7-Scheme 2 as a clear oil. (1.02 g, 74%); TLC r_(f)0.20 (silica 5% methanol/CHCl₃); ¹ H NMR (400 MHz, CDCl₃) δ 0.40 (6H,s), 2.59 (2H, t), 2.75 (2H, t), 2.87 (4H, 2t), 3.66 (3H, s), 3.72 (2H,s), 3.80 (2H, s), 6.69 (2H, d, J=8.4 Hz), 6.87 (2H, d, J=8.6 Hz), 7.01(2H, d, J=8.4 Hz), 7.08 (2H, d, J=8.6 Hz), 7.27 (2H, d, J=7.8 Hz), 7.53(2H, d, J=7.8 Hz).

Methyl3-[[dimethyl-4-[N-[2-(4-hydroxyphenyl)ethyl]acetamidomethyl]-phenylsilyl]methyloxyphenyl]propionate(8-Scheme 2)

To a stirred solution of 7-Scheme 2 (2.0 g, 4.2 mmol) in CH₂ Cl₂ (50 mL)was added acetic anhydride (0.47 mL, 5 mmol) followed by pyridine (0.81mL, 10 mmol). After stirring for 16 h the reaction was evaporated todryness. Purification by flash chromatography (silica, 1-5%methanol/CHCI₃) gave 8-Scheme 2 as a white solid. (1.53 g, 70%); TLCr_(f) 0.41 (silica 5% methanol/ CHCl₃); HPLC: Altex Ultrasphere™ Si(4.6×250mm) 1-10% iPrOH/CHCI₃ linear gradient over 25 min., UV 280 nm,rt 8.15 min., k' 2.2); ¹ H NMR (400 MHz, MeOH-d₄) (amide rotamers) δ0.37, 0.38 (6H, 2s), 1.91, 2.09 (3H, 2s), 2.55 (2H, t), 2.70, 2.74 (2H,2t), 2.81 (2H, t), 3.43, 3.45 (2H, 2t), 3.61 (3H, s), 3.74, 3.75 (2H,2s), 4.44, 4.57 (2H, 2s), 6.69, 6.70 (2H, 2d), 6.83 (2H, d, J=8.6 Hz),6.96, 6.97 (2H, 2d), 7.05 (2H, d, J=8.7 Hz), 7.17, 7.24 (2H, 2d), 7.57,7.60 (2H, 2d).

TFA solution cleavage reaction of 8-Scheme 2

To an aliquot of compound 8-Scheme 2 (300 mg, 0.58 mmol) was added TFA(10 mL). The reaction was stirred for 16 h at room temperature andevaporated to dryness. HPLC analysis [Altex Ultrasphere™ SI (4.6×250 mm)1-10% iPrOH/CHCl₃ gradient over 25 min., 1.5 mL/min., UV at 280 and 254nm] showed only trace amounts of starting material with two majorproducts at rt 3.89 and 15.15 min. The two major products were thenisolated by flash chromatography (silica, 2% methanol/CHCl₃). Theearlier eluting peak (rt 3.89 min.) was identified as methyl3-(4-hydroxyphenyl)propionate 1-Scheme 3 (95 mg, 91 %); ¹ H NMR (400MHz, CDCl₃) δ 2.50 (2H, t), 2.89 (2H, t), 3.68 (3H, s), 5.78 (1H, br s),6.76 (2H, d), 7.04 (2H, d). The later eluting peak (rt 15.15 min.) wasisolated as a white solid and has a structure consistant with thesiloxane dimer 2-Scheme 3 (135 mg, 70%); MS(ES) m/z 669.4 [M+H]⁺ ; IR(nujol) 3162, 1616, 1252, 1045 cm⁻¹ ; ¹ H NMR (400 MHz, MeOH-d₄) (amiderotomers) δ 0.29,0.30 (6H, 2s), 1.91, 2.09 (3H, 2s), 2.71, 2.72 (2H,2t), 3.45, 3.46 (2H, 2t), 4.43, 4.56 (2H, 2s), 4.86 (2H, s), 6.69, 6.71(2H, d, J=7.8 Hz), 6.95, 6.97 (2H, 2d, J=7.8 Hz), 7.13, 7.20 (2H, 2d,J=7.7 Hz), 7.47, 7.50 (2H, 2d, J=7.7 Hz).

HF cleavage reaction of 8-Scheme 2

To compound 8-Scheme 2 (300 mg, 0.58 mmol) in an HF reaction vesselcontaining anisole (1 mL) was distilled HF (9 mL) while cooling at -78°C. The mixture was stirred for 1 h at 0° C. in an ice bath thenevaporated under vacuum to dryness. The residue was placed under highvaccum for several hours to remove excess anisole and analyzed by HPLC.HPLC [Altex Ultrasphere™ SI (4.6×250 mm). 1-10% iPrOH/CHCl₃ gradientover 25 min., 1.5 mL/min., UV at 280 and 254 nm] showed a major productwith a retention time of 8.87 min. as well as small amounts of the twoproducts 1-Scheme 3 and 2-Scheme 3 isolated in the previous TFAreaction. Purification by flash chromatography (silica 2%methanol/CHCl₃) gave the major product as a white solid, identified asthe desired cleavage product 3-Scheme 3 and identical with authenticmaterial by TLC, HPLC, MS(ES) and ¹ H NMR (108.5 mg, 69%); MS(ES) m/z270.4 [M+H]⁺ ; ¹ H NMR (400 MHz, CDCl₃) (amide rotomers) δ 1.88 and 2.12(3H, 2s), 2.74 and 2.78 (2H, 2t), 3.41 and 3.58 (2H, 2t), 4.39 and 4.63(2H, 2s), 6.78 (2H, 2d), 7.95 and 7.01 (2H, 2d), 7.11-7.35 (5H, m).

Dimethyl[dimethyl-4-(triisopropylsilyloxymethyl)phenylsilyl]methyl-malonate(1-Scheme 4)

To a stirred solution of 0.5 M sodium methoxide in methanol (88 mL, 44mmol) were added dimethyl malonate (10 mL, 85 mmol) followed by 3-Scheme2 (18.30 g, 44 mmol). The reaction was heated at reflux to 70° C., underAr, and stirred for 24 h. After cooling to room temperature, thereaction was evaporated to dryness, taken up in ethyl acetate (250 mL),washed with cold aq. 1N hydrochloric acid (250 mL), brine (250 mL),dried (MgSO₄) and evaporated. Purification by flash chromatography(silica, 5% ethyl acetate/hexane) gave 1-Scheme 4 as a clear oil. (14.37g, 70%): TLC r_(f) 0.34 (silica, 10% ethyl acetate/hexane); ¹ H NMR (400MHz, CDCl₃) δ 0.29 6H, s), 1.09 (18H, d, J=6.5 Hz), 1.18 (3H, m), 1.41(2H, d, J=7.9 Hz), 3.36 (1H, t), 3.61 (6H, s), 4.83 (2H, s), 7.35 (2H,d, J=7.9 Hz), 7.46 (2H, d, J=7.9 Hz).

Methyl 3-[dimethyl-4-(hydroxymethyl)phenylsilyl]propionate (2-Scheme 4)

Compound 1-Scheme 4 (14.37 g, 30.8 m ol) was added to a solution of(3:1:1) acetic acid, water, THF (200 mL) and heated to 45° C. Thereaction was stirred for 24 h, cooled and evaporated to dryness.Purification by flash chromatography (silica, 35% ethyl acetate/hexane)gave the benzyl alcohol as a clear oil. (8.31 g, 87%): TLC r_(f) 0.40(silica, 40% ethyl acetate/hexane); ); ¹ H NMR (400 MHz, CDCl₃) δ 0.30(6H, s), 1.42 (2H, d, J=7.7 Hz), 1.66 (1H, br s), 3.35 (1H, t), 3.62(6H, s), 4.69 (2H, s), 7.36 (2H, d, J=7.9 Hz), 7.49 (2H, d, J=7.9 Hz).

To a stirred solution the above alcohol (8.31 g, 26.8 m ol) in DMSO (50mL) were added LiCl (2.27 g, 54 mmol) and water (1.4 mL). After flushingwith Ar the reaction was heated to 140° C. and stirred for 24 h. Thereaction was then cooled to room temperature, taken up in ethyl acetate(250 mL), washed with brine (500 mL), dried (MgSO₄) and evaporated.Purification by flash chromatography (silica, 30% ethyl acetate/hexane)gave 2-Scheme 4 as a clear oil. (5.02 g, 74%): TLC r_(f) 0.41 (silica,30% ethyl acetate/hexane); ¹ H NMR (400 MHz, CDCl₃) δ 0.28 (6H, s), 1.09(2H, ddd), 1.85 (1H, br s), 2.26 (2H, ddd), 3.62 (3H, s), 4.68 (2H, s),7.36 (2H, d, J=8.0 Hz), 7.50 (2H, d, J=8.0 Hz).

Methyl 3-[dimethyl-4-(formyl)phenylsilyl]propionate (3-Scheme 4)

To a stirred solution 2-Scheme 4 (1.16 g, 4.6 mMol) in CH₂ Cl₂ (50 mL)was added MnO₂ (2.0 g, 23 mMol). The reaction was heated to reflux andstirred for 16 h. After cooling to room temperature the reaction wasfiltered through a pad of celite, washed with CH₂ Cl₂, and the filtrateevaporated to dryness to give 3-Scheme 4 as a clear oil. (1.03 g, 89%):TLC r_(f) 0.74 (silica, 30% ethyl acetate/hexane); ¹ H NMR (400 MHz,CDCl₃) δ 0.35 (6H, s), 1.12 (2H, ddd), 2.32 (2H, ddd), 3.62 (3H, s),7.68 (2H, d, J=7.9 Hz), 7.85 (2H, d, J=7.9 Hz), 10.02 (1H, s).

Methyl3-[dimethyl-4-[N-[2-(4-hydroxyphenyl)ethyl]aminomethylphenyl]-silyl]propionate(4-Scheme 4)

To a stirred solution 3-Scheme 4 (1.00 g, 4 mmol) in MeOH (25 mL) wereadded tyramine (0.70 g, 5 mmol) followed by HOAc (0.30 mL, 5 mmol).After stirring for 2 h at room temperature NaBH₃ CN (0.32 g, 5 mmol) wasadded in portions. The reaction was stirred for 16 h and evaporated todryness. Purification by flash chromatography (silica, 95:5 to 90:10CHCl₃ :MeOH) gave 4-Scheme 4 as an oil. (0.94 g, 61%): TLC r_(f) 0.25(silica, 95:5 CHC13:MeOH); ¹ H NMR (400 MHz, CDCl₃) δ 0.28 (6H, s), 1.08(2H, ddd), 2.28 (2H, ddd), 2.77 (2H, t), 2.89 (2H, t), 3.64 (3H, s),3.81 (2H, s), 6.71 (2H, d, J=8.4 Hz), 7.03 (2H, d, J=8.4 Hz), 7.27 (2H,d, J=7.8 Hz), 7.44(2H, d, J=7.8 Hz).

Methyl3-[dimethyl-4-[N-[2-(4-hydroxyphenyl)ethyl]acetamidomethyl-phenyl]silyl]propionate(5-Scheme 4)

To a stirred solution of 4-Scheme 4 (0.94 g, 2.4 mmol) in CH₂ Cl₂ (25mL) were added pyridine (250 μl, 3.1 mmol) followed by acetic anhydride(229 μl, 2.4 mmol). After stirring for 16 h the reaction was taken up inCHCl₃ (50 mL) and washed with cold aq. 1N HCl (50 mL), brine (50 mL),dried (MgSO₄) and evaporated. Purification by flash chromatography(silica, 98:2 to 95:5 CHCl₃ :MeOH) gave 5-Scheme 4 as a clear oil. (1.00g, 95%): TLC r_(f) 0.41 (silica, 95:5 CHCl₃ :MeOH); ¹ H NMR (400 MHz,CDCl₃) (amide rotamers) δ 0.27 and 0.28 (6H, 2s), 1.07 (2H, m), 1.73(1H, s), 1.89 and 2.11 (3H, 2s), 2.27 (2H, ddd), 2.76 and 2.79 (2H, 2t),3.41 and 3.57 (2H, 2t), 3.62 and 3.63 (3H, 2s), 4.38 and 4.61 (2H, 2s),6.76 and 6.79 (2H, 2d, J=8.4 Hz), 6.96 and 7.01 (2H, 2d, J=8.4 Hz), 7.11and 7.23 (2H, 2d, J=7.9 Hz), 7.44 and 7.46 (2H, 2d, J=7.9 Hz).

N-[2-(4-Hydroxyphenyl)ethyl]-N-benzylacetamide (3-Scheme 3) fromcleavage of 5-Scheme 4

To compound 5-Scheme 4 (300 mg, 0.7 mmol) was added trifluoroacetic acid(20 mL). The reaction was stirred at room temperature for 36 h andconcentrated to dryness. HPLC analysis [Zorbax® SIL (4.6×250 mm) 1-10%iPrOH, CHCl₃ gradient over 25 min. UV 280 nm] showed <8% startingmaterial remained. The major product was purified by flashchromatography (silica, 98:2 CHCl₃ :MeOH) to give 3-Scheme 3 (172 mg,91%); TLC r_(f) 0.36 (silica, 95:5 CHCl:MeOH); HPLC: rt 10.75 min. k'4.4 Zorbax®SIL (4.6×250 mm) 1-10% iPrOH/CHCl₃ over 20 min., UV 254 and280 nm; MS(ES) m/z 270.4 [M+H]⁺ ; ¹ H NMR (400 MHz, CDCl₃) (amiderotamers) δ 1.88 and 2.12 (3H, 2s), 2.74 and 2.78 (2H, 2t), 3.41 and3.58 (2H, 2t), 4.39 and 4.63 (2H, 2s), 6.78 (2H, 2d), 7.95 and 7.01 (2H,2d), 7.11-7.35 (5H, m).

3-[Dimethyl-4-[N-[2-(4-hydroxyphenyl)ethyl]acetamidomethylphenyl]-silyl]propionicacid (1-Scheme 5)

To a stirred solution of 5-Scheme 4 (0.67 g, 1.6 mmol) in dioxane (10mL) was added aq. 1N NaOH (3.5 mL). After stirring for 16 h the reactionwas acidified with aq. 1N HCl (3.5 mL) and partially evaporated. Theremaining material was taken up in CHCl₃ (75 mL), washed with brine (75mL), dried (MgSO₄) and evaporated to give 1-Scheme 5 as a white solidfoam. (0.66 g, 100%): TLC r_(f) 0.23 (silica, 95:4:1 CHCI₃ :MeOH:HOAc);1H NMR (400 MHz, CDCl₃) (amide rotomers) δ 0.27 and 0.28 (6H, 2s), 1.07(2H, m), 1.94 and 2.12 (3H, 2s), 2.28 (2H, ddd), 2.74 and 2.77 (2H, 2t),3.40 and 3.53 (2H, 2t), 4.36 and 4.58 (2H, 2s), 6.76 and 6.79 (2H, 2d,J=8.4 Hz), 6.93 and 6.99 (2H, 2d, J=8.4 Hz), 7.10 and 7.21 (2H, 2d,J=7.9 Hz), 7.43 and 7.46 (2H, 2d, J=7.9 Hz).

3-[Dimethyl-4-[N-[2-(4-hydroxyphenyl)ethyl]acetamidomethylphenyl]-silyl]pronionylbenzhydrylamine resin (2-Scheme 5)

To BHA resin (obtained from 1.0 g BHA resin hydrochloride afterneutralization with a solution of 10% Et₃ N in CH₂ Cl₂ and washing withCH₂ Cl₂, 1.06 mMol) in a shaker vessel(Stewart et al., Solid PhasePeptide Synthesis, Pierce Chemical Company: Rockford, Ill., 1984) wereadded a solution of 1-Scheme 5 (0.66 g, 1.59 mmol) in DMF (20 mL)followed by HOBt (0.42 g, 3.1 mMol) and DCC (0.36 g, 1.7 mMol). Thereaction was shaken for 16 h, washed with DMF (2×25 mL), (1:1) CHCl₃:MeOH (2×25 mL), CH₂ Cl₂ (2×25 mL) and dried under vacuum for 24 h togive 2-Scheme 5. (1.36 g): EA %N =2.3 found, 2.4 calc. (0.81 mmol/g),negative Kaiser test.

N-[2-(4-Hydroxyphenyl)ethyl]-N-benzylacetamide (3-Scheme 3) from thesolution phase TFA cleavage of 2-Scheme 5

To resin 2-Scheme 5 (301.5 mg, 244 μmol) was added TFA (20 mL). Thereaction was stirred for 40 h at room temperature, filtered through asintered glass funnel and washed with CHCl₃ (3×5 mL). The filtrate wasevaporated to dryness and dried under vacuum for 24 h to give 3 Scheme 3as an off white solid identical to the authentic material made insolution. (77.6 mg, 100%, 96% by N analysis of recovered resin): TLCr_(f) 0.36 (silica, 95:5 CHCl₃ :MeOH); HPLC: rt 10.75 min. k' 4.4,Zorbax® SIL (4.6×250 mm), 1-10% iPrOH/CHCl₃ over 20 min., UV 254 and 280nm; MS(ES) m/z 270.4 [M+H]⁺ ; ¹ H NMR (400 MHz, CDCl₃) (amide rotomers)δ 1.88 and 2.12 (3H, 2s), 2.74 and 2.78 (2H, 2t), 3.41 and 3.58 (2H,2t), 4.39 and 4.63 (2H, 2s), 6.78 (2H, 2d), 7.95 and 7.01 (2H, 2d),7.11-7.35 (5H, m).

Vapor Phase TFA Cleavage Reaction Studies

To each of four 2 ml sintered glass funnels were placed 100 mg of driedresin 2-Scheme 5. The samples were each washed with CH₂ Cl₂ to swell theresin, then drained mostly dry by vacuum aspiration. Each was thenplaced into a 50 mL beaker, within a TLC chamber containing a layer ofTFA on the bottom. At selected time periods (6, 16, 24 and 40 h) asintered glass funnel with resin was removed and dried under vacuum toremove residual TFA. The resin in each sintered glass funnel was thenwashed twice with a 1 ML solution of 2% methanol in CHCl₃ filtereddirectly into separate vials under vacuum. A 5 μl aliquot of eachfiltrate was then injected into an HPLC and the peak area of the productwas obtained to determine the amount cleaved. The conversion factor forthe peak area to percent cleaved was obtained from the peak area of the40 h resin sample and the percent cleaved obtained from nitrogenanalysis. For multiple TFA cleavages the washed resin after the 6 hreaction was reintroduced into the TFA chamber for another 6 h andreanalysed as above. This was repeated a third time for another 6 hours.(See FIGS. 1 and 2).

3-[Dimethyl-4-(hydroxymethyl)phenylsilyl]propionic acid

To a solution of 2-Scheme 4 (2.50 g, 9.9 mMol) in dioxane (30 mL) wasadded aq. 1N NaOH (15 mL). After stirring for 4 h the reaction wasacidified with aq. 1N hydrochloric acid (15 mL) and evaporated to neardryness. The residue was taken up in ethyl acetate (100 mL), washed withcold aq. 1N HCl (100 mL), brine (100 mL), dried (MgSO₄) and evaporatedto give the free acid as a clear oil. (2.36 g, 100%): TLC r_(f) 0.45(silica, 95:4:1 CHCl₃ :MeOH:HOAc); ¹ H NMR (250 MHz, CDCl₃) δ 0.30 (6H,s), 1.08 (2H, ddd), 2.30 (2H, ddd), 4.68 (2H, s), 7.36 (2H, d, J=7.9Hz), 7.50 (2H, d, J=7.9 Hz).

3-[Dimethyl-4-(hydroxymethyl)phenylsilyl]propionyl benzhydrylamine resin(2-Scheme 6)

To BHA resin (obtained from 7.0 g BHA resin hydrochloride afterneutralization with 10% Et₃ N in CH₂ Cl₂ and washing with CH₂ Cl₂, 7.77mmMol) was added a solution of the above3-[dimethyl-4-(hydroxymethyl)phenylsilyl]propionic acid (2.36 g, 9.9mmol) in DMF (30 mL). To this were added HOBt (2.7 g, 20 mmol) and DCC(2.1 g, 9.9 mmol). The reaction was shaken for 16 h, washed with DMF(2×30 mL), (1:1) CHCl₃ :MeOH (2×30 mL), CH₂ Cl₂ (2×30 mL), hexane (30mL) and dried under vacuum for 24 h to give resin 2-Scheme 6. (8.66 g,0.90 mmol/g): negative ninhydrin test; (Kaiser et al., Anal. Biochem.1970, 34, 594-598). MAS ¹ H NMR (500 Mhz) δ 0.20 (6H, Si(CH₃)₂ 's), 1.05(2H, CH₂ CON), 2.10 (2H, SiCH₂ C), 2.80 (1H, HO), 4.52 (2H, OCH₂ --Ar),7.22, 7.40 (4H, ArH's).

3-[Dimethyl-4-(bromomethyl)phenylsilyl]propionyl benzhydryl amine resin(3-Scheme 6)

To resin 2-Scheme 6 (1.60 g, 1.44 mmol) in a shaker vessel were addedTHF (30 mL), CBr₄ (0.96 g, 2.88 mmol) and Ph₃ P (0.76 g, 2.88 mmol). Thereaction was shaken for 16 h, washed with THF (2×30 mL), ethanol (2×30mL), CH₂ Cl₂ (2×30 mL), hexane (30 mL) and dried under vacuum for 16 hto give resin 3-Scheme 6. (1.76 g, 0.84 mMol/g): EA % N found 1.18,calc. 1.22; % Br found 6.62, calc. 6.95.

3-[Dimethyl-4-[N-[2-(4-hydroxyphenyl)ethyl]aminomethylphenyl]silyl]-propionylbenzhydrylamine resin (4-Scheme 6)

To resin 3-Scheme 6 (1.50 g, 1.26 mmoL) in a shaker vessel were addedDMF (20 mL), tyramine (1.7 g, 12.4 mmol) and Et₃ N (1.8 mL, 12.9 mmol).The reaction was shaken for 16 h, washed with DMF (2×20 mL), MeOH (2×20mL), CH₂ Cl₂ (2×20 mL), hexane (20 mL) and dried under vacuum for 16 hto give resin 4-Scheme 6. (1.52 g, 0.72 mmol/g): EA % N found 2.01 calc2.33; MAS ¹ H NMR (500 MHz) δ 0.20 (6H, Si(CH₃)₂ 's), 1.10 (2H, CH₂CON), 2.20 (2H, SiCH₂ C), 2.70 (CH₂ Ar), 2.82 (2H, NCH₂ C), 3.74 (2H,NCH₂ Ar), 6.71, 6.90, 7.18, 7.40 (8H, ArH's).

3-[Dimethyl-4-[N-[2-(4-hydroxyphenyl)ethyl]acetamidomethylphenyl]-silyl]propionylbenzhydrylamine resin (5-Scheme 6)

To resin 4-Scheme 6 (1.0 g, 0.72 mMol) in a shaker vessel were added CH₂Cl₂ (20 mL), pyridine (60 μl, 0.74 mmol) and acetic anhydride (70 μl,0.74 mmol). The reaction was shaken for 16 h, washed with CH₂ Cl₂ (2×20mL), MeOH (2×20 mL), CH₂ Cl₂ (20 mL), hexane (20 mL) and dried undervacuum for 16 h to give resin 5-Scheme 6. (1.07 g): MAS ¹ H NMR (500MHz) (amide rotamers) δ0.19 (6H, Si(CH₃)₂ 's), 1.02 (2H, CH₂ CON), 1.80,1.95 (3H, CH₃ CON), 2.15 (2H, SiCH₂ C--), 2.63, 2.70 (2H, CH₂ Ar), 3.29,3.45 (2H, NCH₂ C), 4.22, 4.49 (2H, NCH₂ Ar), 6.70, 6.81, 6.89, 7.3(8H,ArH's). TFA vapor cleavage of this resin 5-Scheme 6 for 72 h at roomtemperature gave a 72 % isolated yield of 3 Scheme 3, identical by HPLC,TLC, MS(ES) and ¹ H NMR with authentic material. A small amount (<5%) ofthe diacetylated material was also obtained after cleavage.

3-[Dimethyl-4-[N-[2-(4-N',N'-dimethylaminoethyloxyphenyl)ethyl]acetamido-methylphenyl]silyl]propionylbenzhydrylamine resin (6-Scheme 6)

To resin 5-Scheme 6 (0.87 g, 0.58 mmol) in a shaker vessel were addeddry THF (15 mL), N,N-dimethylaminoethanol (0.58 mL, 5.8 mmol), Ph₃ P(0.76 g, 2.9 mmol) and DIAD (0.57 mL, 2.9 mmol). The reaction was shakenunder an Ar atmosphere for 4 h and filtered dry under Ar. The reactionwas repeated an additional time for 16 h, washed with THF (2×15 mL),MeOH (2×15 mL), CH₂ Cl₂ (2×15 ml), hexane (15 mL) and dried under vacuumfor 16 h to give resin 6-Scheme 6. (0.94 g, 0.67 mmol/g); MAS ¹ H NMR(500 MHz) (amide rotamers) δ 0.21 (6H, Si(CH₃)₂ 's), 1.08 (2H, CH₂ CON),1.95,2.05 (3H, CH₃ CON), 2.19 (2H, SiCH₂ C), 2.32 (6H, N(CH₃)₂ ¹ s),2.72 (2H, ArOCH₂ C), 2.80 (2H, CH₂ Ar), 3.36, 3.52 (2H, NCH₂ C), 4.02(2H,CCH₂ N), 4.30, 4.58 (2H, NCH₂ Ar), 6.80, 6.90, 7.14, 7.47 (8H,ArH's).

N-[2-(4-N',N'-dimethylaminoethyloxyphenyl)ethyl]-N-benzylacetamide(7-Scheme 6)

Resin 6-Scheme 6 (200 mg, 134 μmol) was exposed to TFA vapor at roomtemperature for 72 h and dried under vacuum. Extraction with (1: 1)CHCl₃ :MeOH (4×2 mL), evaporation of the filtrate and drying undervacuum for 24 h gave 7-Scheme 6 as its TFA salt. (67.2 mg, 100%): TLCr_(f) 0.23 (silica, 9:1 CHCl₃ :MeOH); MS(ES) m/z 341.0 [M+H]⁺ ; ¹ H NMR(400 MHz, CDCl₃) (amide rotomers) δ 1.92 and 2.12 (3H, 2s), 2.77 and2.82 (2H, 2t), 2.98 (6H, s), 3.49 (2H, t), 3.58 (2H, m), 4.33 (2H, t),4.53 and 4.60 (2H, 2s), 6.94 and 6.97 (2H, 2d, J=8.5 Hz), 7.13 and 7.14(2H, 2d, J=8.5 Hz), 7.19-7.38 (5H, m).

What is claimed is:
 1. A method for preparing a resin-bound compound,wherein the compound is an aromatic carbocycle comprising an aromaticcarbon atom and at least one substituent, X, A, B or C, said methodcomprising the steps of:(i) coupling the aromatic carbon to a polymericresin support through a silane linker to give a resin-bound aryl silaneintermediate of formula (I): ##STR9## wherein: R^(a) and R^(b),independently from one another, are C₁ to C₆ alkyl; X, A, B and C are,independently from one another, hydrogen, halogen, alkyl, alkenyl,alkynyl, alkoxy, alkylthio, C(O)R^(d), wherein R^(d) is hydrogen oralkyl, t-butoxyaminocarbonyl, cyano, nitro, aryl, heteroaryl, arylalkyl,alkyl disulfide, aryl disulfide, acetal, fluorenylmethoxycarbonyl ororthoester group; and n is an integer from 2 to 20; and (ii) performingadditional synthetic chemistry on at least one substituent, X, A, B orC, in order to modify said substituent, with the proviso that not all ofsubstituents X, A, B or C are hydrogen and not all of X, A, B or C arealkyl.
 2. The method of claim 1 wherein the silane linker is--C(O)--(CH₂)_(n) --Si--R^(a) R^(b), wherein R^(a) and R^(b) areindependently, C₁ to C₆ alkyl, and n is an integer from 2 to
 20. 3. Themethod of claim 2 wherein R^(a) and R^(b) are independently, C₁ to C₄alkyl.
 4. The method of claim 2 wherein R^(a) and R^(b) are both methylor ethyl.
 5. The method of claim 2 wherein R^(a) and R^(b) are bothmethyl.
 6. The method of claim 1 wherein n is the integer
 3. 7. Themethod of claim 1 wherein the polymeric resin support is a cross-linkedpolystyrene resin, a polyethylene glycol-polystyrene resin, or apolypropylene glycol resin.
 8. The method of claim 1 wherein after step(ii), the method further comprises the step of cleaving the resin-boundaryl silane intermediate so that the aromatic carbocycle resulting fromthe cleavage has a hydrogen on the aromatic carbon where it was boundthrough the silane linker.
 9. The method of claim 1 wherein the aromaticcarbon is first coupled to the silane linker.
 10. The method of claim 8wherein the aromatic carbocycles are cleaved from the polymeric resinsupport by treatment with trifluoroacetic acid.
 11. A method forpreparing a library of diverse resin-bound aromatic carbocycles eachcomprising an aromatic carbon atom and at least one substituent, X, A, Bor C, said method comprising the steps of:(i) coupling the aromaticcarbon atom of each of a plurality of aromatic carbocycles to anindividual polymeric resin support through a silane linker to give aplurality of resin-bound aryl silane intermediates of formula (I)##STR10## wherein: R^(a) and R^(b), independently from one another, areC₁ to C₆ alkyl; X, A, B and C are, independently from one another,hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio,C(O)R^(d), wherein R^(d) is hydrogen or alkyl, t-butoxyaminocarbonyl,cyano, nitro, aryl, heteroaryl, arylalkyl, alkyl disulfide, aryldisulfide, acetal, fluorenylmethoxycarbonyl or orthoester group; and nis an integer from 2 to 20; (ii) optionally dividing said resin-boundaryl silane intermediates into a plurality of portions; (iii) performingadditional synthetic chemistry on at least one of the substituents, X,A, B or C contained on the plurality of aromatic carbocycles, in orderto modify said substituent; and (iv) optionally recombining theportions, with the proviso that not all of substituents X, A, B or C arehydrogen and not all of X, A, B or C are alkyl.
 12. The method of claim11 wherein the steps of (ii) dividing the portions, (iii) performingadditional synthetic chemistry, and (iv) recombining the portions, arecarried out more than once.
 13. The method of claim 12, wherein afterstep (iv), the method further comprises the step of partially cleavingthe aromatic carbocycles from the individual polymeric resin supports sothat the aromatic carbocycles resulting from the cleavage have ahydrogen on the aromatic carbon where they were bound to the polymericresin support through the silane linker.
 14. The method of claim 13wherein the derivatized aromatic carbocycles are fully cleaved from theresin.
 15. The method of claim 11 wherein the polymeric resin support isa cross-linked polystyrene resin, a polyethylene glycol-polystyreneresin, or a polypropylene glycol resin.
 16. The method of claim 14wherein the aromatic carbocycles are cleaved from the polymeric resinsupport by treatment with trifluoroacetic acid.
 17. The method of claim11 wherein each of the plurality of aromatic carbocycles is attached tothe polymeric resin support by a silane linker comprising--C(O)--(CH₂)_(n) -Si-R^(a) R^(b), wherein R^(a) and R^(b) areindependently, C₁ to C₆ alkyl, and n is an integer from 2 to
 20. 18. Themethod of claim 17 wherein R^(a) and R^(b) are independently, C₁ to C₄alkyl.
 19. The method of claim 17 wherein R^(a) and R^(b) are bothmethyl or ethyl.
 20. The method of claim 17 wherein R^(a) and R^(b) areboth methyl.
 21. The method of claim 17 wherein n is the integer
 3. 22.A compound of Formula (I): ##STR11## wherein: R^(a) and R^(b),independently from one another, are C₁ to C₆ alkyl;X, A, B and C are,independently from one another, hydrogen, halogen, alkyl, alkenyl,alkynyl, alkoxy, alkylthio, C(O)R^(d), wherein R^(d) is hydrogen oralkyl, t-butoxyaminocarbonyl, cyano, nitro, aryl, heteroaryl, arylalkyl,alkyl disulfide, aryl disulfide, acetal, fluorenylmethoxycarbonyl ororthoester group, provided that X, A, B and C can not all be hydrogenand X, A, B and C can not all be alkyl; and n is an integer from 2 to20.